Systems, Methods, and compositions for achieving closure of suture sites

ABSTRACT

Systems and methods employ functional instruments to close incisions and wounds using a suture knot in combination with a biocompatible material composition. The systems and methods are well suited for use, for example, at a vascular puncture site following a vascular access procedure.

RELATED APPLICATIONS

This application is a division of copending U.S. patent application Ser.No. 10/212,472, filed Aug. 5, 2002, and entitled “Systems, Methods, andCompositions for Achieving Closure of Suture Sites” (now U.S. Pat. No.7,351,249), which is continuation-in-part of U.S. patent applicationSer. No. 10/141,510, filed May 8, 2002 and entitled “Systems, Methods,and Compositions for Achieving Closure of Vascular Puncture Sites,”which is a continuation-in-part of U.S. patent application Ser. No.09/780,843, filed Feb. 9, 2001, and entitled “Systems, Methods, andCompositions for Achieving Closure of Vascular Puncture Sites” (now U.S.Pat. No. 6,949,114), which is a continuation-in-part of U.S. patentapplication Ser. No. 09/283,535, filed Apr. 1, 1999, and entitled“Compositions, Systems, And Methods For Arresting or ControllingBleeding or Fluid Leakage in Body Tissue” (now U.S. Pat. No. 6,458,147),which is itself a continuation-in-part of U.S. patent application Ser.No. 09/188,083, filed Nov. 6, 1998 and entitled “Compositions, Systems,and Methods for Creating in Situ, Chemically Cross-linked, MechanicalBarriers” (now U.S. Pat. No. 6,371,975), all of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The invention generally relates to the systems and methods for closingsuture sites in body tissue to affect desired therapeutic results.

BACKGROUND OF THE INVENTION

There are many therapeutic indications today that pose problems in termsof technique, cost efficiency, or efficacy, or combinations thereof.

For example, following an interventional procedure, such as angioplastyor stent placement, a 5 Fr to 9 Fr arteriotomy remains. Typically, thebleeding from the arteriotomy is controlled through pressure applied byhand, by sandbag, or by C-clamp for at least 30 minutes. While pressurewill ultimately achieve hemostasis, the excessive use and cost of healthcare personnel is incongruent with managed care goals.

Various alternative methods for sealing a vascular puncture site havebeen tried. For example, devices that surgically suture the puncturesite percutaneously have been used. Suture is used because it isperceived as providing a reliable and tight closure of any wound wherethe suture can be properly placed, tied, and tightened. Suturing isrelatively straightforward in most open surgical procedures. However,placement and tying of sutures in closed, minimally invasive procedures,e.g., in laparoscopic or catheter-based procedures, often requireplacement, tying, and tightening of a suture knot transcutaneouslythrough a tissue tract. A variety of devices have been developed for thetranscutaneous placement, tying, and tightening of suture knots througha tissue tract.

For example, when used for closure of vascular punctures, these devicesdeploy within a tissue tract to place a suture loop through tissue onopposite sides of the vascular puncture. Two free ends of the sutureloop are brought out through the tissue tract. The loops are externallytied by the attending physician, forming a sliding knot in the sutureloop. A tool, called a “knot pusher,” is deployed through the tissuetract for cinching the slidable knot over the loop. When used to suturevessel punctures, the knot pusher advances the knot through the tissuetract to locate the knot over the adventitial wall of the blood vessel,resulting in puncture edge apposition.

Despite the skill and due care involved in placing, tying, andtightening a suture knot using these devices, seepage of blood andfluids at the suture site and into the tissue tract can still occur.Under these circumstances, a “dry” femoral closure cannot be achieved.Hematoma formation can result, which can prolong a patient's return toambulatory status without pain and immobilization.

Thus, there remains a need for fast and straightforward systems andmethods to achieve suture closure through a tissue tract, which aresubstantially free of blood or fluid leakage about the suture site andinto the tissue tract.

SUMMARY OF THE INVENTION

One aspect of the invention provides systems and methods for sealing asuture knot. The systems and methods form a suture knot and discharge aliquid closure material adjacent the suture knot. The liquid closurematerial reacts after discharge to form a solid closure adjacent thesuture knot. In one embodiment, a knot pusher is used to form the sutureknot, and the liquid closure material is discharged through the knotpusher.

The systems and methods can be used for sealing a puncture site in ablood vessel.

Another aspect of the invention provides a knot pusher comprising a bodyincluding a passage having a distal end. The body is sized andconfigured to engage a suture knot adjacent the distal end of thepassage. A fitting is carried by body. The fitting is sized andconfigured for introducing a liquid closure material into the passagefor discharge through the distal end adjacent the suture knot. Theliquid closure material reacts after discharge to form a solid closureadjacent the suture knot.

In one embodiment, the body of the knot pusher is sized and configuredfor locating the suture knot in a tissue puncture tract.

In one embodiment, the body of the knot pusher is sized and configuredfor locating the suture knot adjacent a puncture site in a blood vessel.

Another aspect of the invention provides an assembly for sealing apuncture site in a blood vessel. The assembly comprises a suture knotformed at the puncture site, and a dispenser to discharge a liquidclosure material adjacent the suture knot. The liquid closure materialreacts after discharge to form a solid closure adjacent the suture knot.

In one embodiment, the liquid closure material comprises a firstcomponent including an electrophilic polymer material having afunctionality of at least three; a second component including anucleophilic material that, when mixed with the first component andafter discharge as a liquid, cross-links with the first component toform the solid closure, a non-liquid, three-dimensional barrier; and abuffer material mixed with the second component. The first component caninclude a multi-armed polymer structure, such as, e.g., poly(ethyleneglycol), poly(ethylene oxide), poly(vinyl alcohol),poly(vinylpyrrolidinone), poly(ethyloxazoline), and poly(ethyleneglycol)-co-poly(propylene glycol) block copolymers. The second componentcan include hydrophilic protein, such as, e.g., serum, serum fractions,solutions of albumin, gelatin, antibodies, fibrinogen, serum proteins,and recombinant or natural human serum albumin. The buffer material caninclude, e.g., tris-hydroxymethylaminomethane and/or sodium carbonateanhydrous.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plane view of a system of functional instruments, withportions broken away and in section, for the closure of incisions andwounds using a suture knot in combination with a biocompatible materialcomposition, the system including a knot pusher and a componentintroducer/mixer assembly.

FIG. 2 is a side view of the knot pusher that forms a part of the systemshown in FIG. 1.

FIG. 3 is a side section view of the knot pusher that forms a part ofthe system shown in FIG. 1.

FIG. 4 is a side view of a mixing element, which forms a part of thesystem shown in FIG. 1, coupled for use to the knot pusher shown inFIGS. 2 and 3.

FIGS. 5 to 11 illustrate the use of the formative component assembly,that forms a part of the system shown in FIG. 1, to deliver a closurecomposition to the knot pusher shown in FIGS. 2 and 3, wherein FIGS. 5and 6 are perspective views illustrating the insertion of the vialcomponent of the formative component assembly; FIG. 7 is a perspectiveview illustrating the insertion of the syringe component of theformative component assembly; FIG. 8 is a side section view illustratingthe coupling the assembled formative component assembly to the mixerelement, which, in turn, is coupled to the knot pusher shown in FIGS. 2and 3; FIG. 9 is a side section view illustrating the advancement of thesyringe plunger component of the formative component assembly andfurther illustrating the transfer of the liquid component in the syringeinto the vial containing the solid component mixture of the liquid andthe reconstituted solid components in the vial; FIG. 10 is a sidesection view illustrating the urging of the mixture from the vialthrough the second needle component of the formative component assemblyand into the mixer element; and FIG. 11 is a side section viewillustrating the syringe and vial after the mixture has been transferredfrom the vial to the mixer element.

FIG. 12 is a plane view of a system of functional instruments for theclosure of incisions and wounds using a suture knot in combination witha biocompatible material composition, the system including a knot pusheras generally shown in FIGS. 2 and 3 and an alternative embodiment ofcomponent introducer/mixer assembly comprising two syringes coupled to aholder.

FIG. 13 is a plane exploded view of the component introducer/mixerassembly shown in FIG. 12, with one of the syringes withdrawn from theholder.

FIG. 14 is an assembled view of the component introducer/mixer assemblyshown in FIG. 13.

FIG. 15 is a plane view of the component introducer/mixer assembly shownin FIG. 12 coupled for use to the knot pusher shown in FIGS. 2 and 3.

FIG. 16 is a diagrammatic view of blood vessel puncture site formed toenable the delivery of a diagnostic or therapeutic instrument through avascular sheath, after removal of the diagnostic or thereapeuticinstrument and the placement of a suture loop through the puncture site.

FIG. 17 is a diagrammatic view of the blood vessel puncture site shownin FIG. 16, after formation of a slidable knot in the suture loop.

FIG. 18 is a diagrammatic view of the blood vessel puncture site shownin FIG. 17, showing the threading of suture in the knot pusher afterformation of the slidable knot.

FIG. 19 is a diagrammatic view of the blood vessel puncture site shownin FIG. 18, after threading of suture in the knot pusher and as the knotpusher is advanced toward the tissue tract, pushing the slidable knot.

FIGS. 20 and 21 are diagrammatic views of the blood vessel puncture siteshown in FIG. 19, as the knot pusher is advanced through the tissuetract to form a suture closure at the vessel puncture site.

FIGS. 22 and 23 are diagrammatic views of the blood vessel puncture siteshown in FIGS. 20 and 21, as a closure composition is being deliveredthrough the knot pusher to envelope the suture closure and fill thetissue tract.

FIG. 24 is a diagrammatic view of the blood vessel puncture site shownin FIGS. 222 and 23, after removal of knot pusher and after the closurecomposition has formed a barrier to seal the suture closure and tissuetract.

FIG. 25 is a side view, with portions broken away and in section showingan alternative embodiment of a knot pusher usable in association withthe system shown in FIG. 1, the knot pusher including an outer sheathand a knot pushing element capable of being inserted coaxially throughthe outer sheath.

FIG. 26 is a diagrammatic view of blood vessel puncture site formed toenable the delivery of a diagnostic or therapeutic instrument through avascular sheath, after removal of the diagnostic or thereapeuticinstrument and the formation of a slidable knot in a suture loop placedthrough the puncture site, and as a suture is being threaded in the knotpusher shown in FIG. 25.

FIG. 27 is a diagrammatic view of the blood vessel puncture site shownin FIG. 26, after threading of suture in the knot pusher and as the knotpusher is advanced toward the tissue tract, pushing the slidable knot.

FIG. 28 is a diagrammatic view of the blood vessel puncture site shownin FIG. 27, as the knot pusher is advanced through the tissue tract toform a suture closure at the vessel puncture site.

FIGS. 29 and 30 are diagrammatic views of the blood vessel puncture siteshown in FIG. 28, as a closure composition is being delivered throughthe knot pusher to envelope the suture closure and fill the tissuetract.

FIG. 31 is a section view of the knot pusher shown in FIG. 26, takengenerally along line 31-31 in FIG. 26 with the knot pushing elementcoaxially advanced through the outer sheath and forming between them apassage through which the closure composition is delivered to envelopethe suture closure and fill the tissue tract, as FIGS. 29 and 30 show.

DETAILED DESCRIPTION

Although the disclosure hereof is detailed and exact to enable thoseskilled in the art to practice the invention, the physical embodimentsherein disclosed merely exemplify the invention that may be embodied inother specific structure. While the preferred embodiment has beendescribed, the details may be changed without departing from theinvention, which is defined by the claims.

The systems and methods disclosed herein are shown in the particularcontext of closing a vascular puncture site. That is because the systemsand methods are well suited for use in this indication, and thisindication thus provides a representative embodiment for purposes ofdescription. Still, it should be appreciated that the systems andmethods described can, with appropriate modification (if necessary), beused for diverse other indications as well, and in conjunction withdelivery mechanisms that are not necessarily catheter-based. Forexample, the systems and methods can be used with delivery mechanismswhich use cannulas, e.g., for the purpose of filling tissue voids oraneurysms, or for tissue augmentation. As yet another example, thesystems and methods can be used to deliver drug or cells to targetedlocations.

I. System Overview

FIG. 1 shows a system 10 of functional instruments for the closure ofincisions and wounds using a suture knot in combination with abiocompatible material composition. The system 10 is well suited foruse, for example, at a vascular puncture site following a vascularaccess procedure.

As arranged in FIG. 1, the system 10 includes a knot pusher 12 and acomponent introducer/mixer assembly 30.

In use (as will be described in greater detail later), the knot pusher12 is sized and configured to be manually deployed during the course ofa surgical procedure where a suture loop has been formed in tissue, toclose an incision or wound, or for any other purpose. In suchprocedures, a slidable knot is formed in the suture loop, and the knotpusher 12 is used to engage and advance the knot to close the loop.

Also in use (as will be described in greater detail later), thecomponent introducer/mixer assembly 30 is sized and configured duringthe course of such surgical procedures, to be coupled to the knot pusher12 to introduce a biocompatible material composition through the knotpusher 12 into contact with the suture knot in situ. The biocompatiblematerial composition produces a solid, three dimensional matrix aboutthe suture knot. The matrix prevents seepage or leakage of blood andfluids in the area of the suture knot.

The system 10 thereby makes possible, through a combination of suturing,augmented by the deposit of a biocompatible matrix material, a drysuture closure, which is substantially free of blood or fluid leakage.

A. The Knot Pusher

As shown in FIGS. 1 to 3, the knot pusher comprises an elongated body orshaft 14. In the illustrated embodiment, the shaft 14 is sized andconfigured for passage through a transcutaneous tissue tract to a vesselpuncture site. As shown in FIG. 16, the tissue track 34 typically willhave been previously formed by a vascular introducer or cannula, throughwhich a desired therapeutic or diagnostic instrument is first introducedthrough a puncture site 36 into the vessel, e.g., to perform coronaryangioplasty. After performing the intended procedure, the therapeutic ordiagnostic instrument and introducer are withdrawn, leaving the puncturesite 36 and the tissue track 34.

For use in this indication, the shaft 14 will typically have a length inthe range from about 7 cm to 10 cm. Furthermore, for use in thisindication, the outside diameter of the shaft 14 is desirably sized toseal the tissue track 34 through which it is introduced (see FIG. 21),so that its presence is hemostatic. In this context, the outsidediameter of the shaft 14 is desirably selected to match the outsidediameter of the vascular introducer, e.g., from 6 Fr. to 10 Fr, so thatthe shaft 14, when deployed, will block substantial flow of blood andfluid from the puncture site 36 up the tissue track 34 (as shown inFIGS. 20 and 21).

As shown in FIG. 3, an interior passage 20 extends through the shaft 14.One end of the passage 20 exits the distal end 16 of the shaft 14. Aside wall slot 22 formed on the distal end 16 opens into the passage 20.

In this arrangement, the knot pusher 12 includes a suture threadingfixture 24. The fixture 24 is releasably carried by the distal end 16 ofthe shaft 14 in alignment with with the slot 22. The fixture 24 includesa threader 26. The threader 26 desirably comprises a loop of thin,flexible wire that is initially positioned so as to pass through theslot 22, into the passage 20, and out the distal end 16 of the shaft 14.

The fixture 24 (see FIGS. 18 and 19) is configured to thread suture Sithrough the passage 20 and slot 22 and thereby engage and advance aslidable knot 18 in the tissue tract 34 (see FIG. 20). The slidable knot18 will have been previously formed (see FIGS. 16 and 17) in a sutureloop 20 placed at the puncture site 36, e.g., using a device describedin U.S. Pat. No. 5,417,699 or U.S. Pat. No. 5,527,322, which are bothincorporated herein by reference. As FIGS. 16 and 17 show, the slidableknot 18 is formed after formation of the suture loop 52 by tying the twofree ends S1 and S2 of suture forming the loop 52.

More particularly, after the slidable knot 18 is formed, the threadingfixture 24 threads a free end S1 through the passage 20 and slot 22 ofthe knot pusher 12. Using the treading fixture 24, the attendingphysician captures a free end S1 of the suture within the loop of thethreader 26 (FIG. 18). The physician disconnects the fixture 24 from theshaft 14, and pulls the fixture 24 distally to draw the threader 26 and,with it, the free end S1 of the suture through the distal shaft end 16into the passage 20, and then through the slot 22 (FIG. 19). Uponreleasing the free end S1 of the suture from the threader 26, anddiscarding the fixture 24, the physician can then urge the knot pusher12 through the tissue tract 34, while holding the free suture end S1, toadvance and tighten the slidable knot 18 within the tissue tract 34, asFIGS. 20 and 21 show. The knot pusher 12 engages and advances theslidable knot 18 over the free end S1 of the suture, to close the loop20 and bring the edges of the puncture site 36 into apposition. Theslidable knot 18 can then be tightened by pulling on the other free endS2 of the suture, forming a suture closure 28 (shown in FIG. 21).

B. The Component Introducer/Mixer Assembly

Upon forming the suture closure 28 using the knot pusher 12 in themanner just described, the component introducer/mixer assembly 30 isassembled and coupled to the knot pusher 12 (see FIG. 22). In use (seeFIGS. 22 and 23), the assembly 30 places a biocompatible materialcomposition 50 about the suture closure 28 outside the blood vessel and,desirably, at least partially up the tissue tract 34 from the puncturesite 36. Most desirably, at the end of the procedure, the composition 50fills the tissue tract 34, as FIG. 24 shows. The biocompatible materialcomposition 50 desirably produces a solid, three dimensional matrix thatprevents seepage of blood and fluids through the suture closure 28 andup the tissue tract 34. The system 10 thereby creates a dry closure,which is substantially free of blood or fluid leakage about the sutureclosure 28 and in the tissue tract 34.

The biocompatible material composition 50 can take various forms.Desirably, the biocompatible material composition 50 is comprised of twoor more formative components which are mixed by the assembly 30 andintroduced in a liquid state through the knot pusher 12 transcutaneouslyto the suture closure 28. Upon mixing, the formative components react,in a process called “gelation,” to transform in situ from the liquidstate, to a semi-solid (gel) state, and then to the biocompatible solidstate.

In the solid state, the composition 50 takes the form of a non-liquid,three-dimensional network. Desirably, the solid material composition 50exhibits adhesive strength (adhering it to adjacent tissue), cohesivestrength (forming a mechanical barrier that is resistant to bloodpressure and blood seepage), and elasticity (accommodating the normalstresses and strains of everyday activity). These properties alone canprovide an effective closure to the vascular puncture site, without useof a suture closure 28. However, when used with a suture closure 28, theproperties of the composition 50 serve to significantly enhance andaugment the localized closure properties of the suture itself.

The solid material composition 50 is also capable of transforming overtime by physiological mechanisms from the solid state to a biocompatibleliquid state, which can be cleared by the body, in a process called“degradation.”

The components forming the material composition 50 can vary. Generallyspeaking, however, the components will include a solid component and aliquid component, which serves as a diluent for the solid component.Mixing of these two components initiates a chemical reaction, by whichthe liquid mixture transforms into a solid composition.

A port 32 on the knot pusher 12 (see FIGS. 1 to 3) communicates withproximal end of the passage 20. The port 32 permits coupling of thecomponent introducer/mixer assembly 30 to the knot pusher 12 (see FIG.22).

The assembly 30 itself can be variously constructed. In the embodimentshown in FIG. 1, the introducer/mixer assembly 30 includes a mixingassembly 38 and a formative component assembly 40. It is the purpose ofthe mixing assembly 38 and the formative component assembly 40 tofacilitate the mixing of components for delivery through the knot pusher12 to the suture closure 28.

1. The Mixing Element

The mixing assembly 38 (see FIGS. 1 and 4) couples at one end to theport 32 of the knot pusher 12, to thereby establish communication withthe interior passage 20. The other end of the mixing assembly 38includes a luer fitting 42 that, in use, couples to the formativecomponent assembly 40 (see FIG. 8), to thereby establish communicationbetween the assembly 40 and the interior passage 20 through the mixingassembly 38.

In the illustrated embodiment (as best shown in FIG. 1), the mixingassembly 38 includes, in the direction of flow from the formativecomponent assembly 40 toward the passage 20, an in-line syringeactivated check valve 44, an in-line mixer 46, and an in-line airaccumulator 48.

The in-line syringe activated check valve 44 can take various forms. Inthe illustrated embodiment, the valve 44 takes the form of aconventional, needleless slip luer lock valve made by Qosina (Edgewood,N.Y.), Product Number 80360. The valve 44 is normally closed to preventback flow of blood or other liquid material through the assembly 38.Back flow of blood, in particular, from the passage 20 toward theformative component assembly 40 is undesirable, because it creates thepotential for blood contact and deposits material that can interfere orcompete with the desired reaction between the liquid components thatform the material composition. Connection of a conventional luer fittingcarried by the formative component assembly 38 (for example, fitting 132shown in FIGS. 1 and 9) opens the valve 44 to allow the introduction ofthe liquid components that form the material composition.

The components of the material composition come into intimate mixingcontact in the liquid state in the in-line mixer 46. In this way,effective mixing can be achieved outside the knot pusher 12. Thus,mixing is not entirely dependent upon the dimensions or lengths of theflow paths within the knot pusher 12. The mixer 46 comprises a mixingstructure, which can vary. For example, the mixer 46 can comprise aspiral mixer manufactured by TAH Industries, Inc. (Robbinsville, N.J.),Part Number 121-090-08.

The in-line air accumulator 48 comprises a chamber that has an interiorvolume sized to trap air that can reside in the material compositionapplicator at time of use.

2. The Formative Component Assembly

In the illustrated embodiment (see FIGS. 1 and 8), the formativecomponent assembly 40 comprises a unitary applicator 92 in which a vial94 holding a solid component 96 and a syringe 98 holding a liquidcomponent 100 can be placed and kept separate in interior compartments.

Axial advancement of the syringe plunger 102 (see FIG. 9) propels theliquid 100 into the vial 94 and brings the two components 96 and 100together within the vial 94 by placing the solid component 96 intosuspension within the liquid component 100. The force created by thisprocess also urges the liquid suspension into the mixing assembly 38 forfurther mixing and delivery through the knot pusher passage 20.

The applicator 92 includes a partition 104 (see FIG. 1) that divides theapplicator 92 into a first compartment 106 and a second compartment 108,each having an open end 110. The first compartment 106 is sized andconfigured to receive and hold the vial 94. The first compartment 106includes a flanged end region 112 that serves to support the applicator92 in an upright position (e.g., standing on a table). The flangedregion 112 further serves to receive a cap 114, as will be described ingreater detail later. The second compartment 108 is sized and configuredto receive and hold the syringe 98. The applicator 92 can be made of anysuitable inert, rigid plastic or metal material. In a representativeembodiment, the first compartment 106 is, e.g., 2½ inches long, thesecond compartment 108 is 2 inches long, and the applicator 92 is 1 inchhigh. This arrangement readily accommodates a conventional vial 94 and aconventional syringe 98.

The syringe 98 can be a conventional syringe 98 having a plunger 102.The dispensing end 116 includes a luer fitting 118. The syringe 98 isaseptically pre-filled with the liquid component 100 and a cap 119 isplaced over the dispensing end 116 to prevent leakage and evaporation ofthe contents.

As FIG. 1 shows, a first needle 120 extends along the central line axisof the applicator 92 and couples the syringe 98 to the vial 94 via aluer fitting 122 that mates with the luer fitting 118 on the syringe 98(also see FIG. 7). The needle 120 thereby provides communication betweenthe first and second compartments 106 and 108. Desirably, the needle 120includes a plurality of side holes lhat serve to uniformly introduce thecontents of the syringe 98 into the vial 94 (see FIG. 9).

As FIG. 1 shows, a second needle 126 is offset from the central lineaxis of the applicator 92 and serves to couple the vial 94 to a moldedpassage 128 that traverses the wall of the second compartment 108. Themolded passage 128 is coupled to the proximal end of a length offlexible tubing 130. The distal end of the tubing 130 includes a luerfitting. 132 adapted to couple to the luer fitting 42 on the mixingassembly 38, as already described. his arrangement provides fluidcommunication between the vial 94 and the mixing assembly 38.Optionally, an in-line air vent 131 (shown in phantom lines in FIG. 1),made, e.g., from a sintered plastic material, can be located in thetubing 130, or otherwise placed in communication with the tubing 130, toallow residual air to vent from fluid prior to entering the mixingassembly 38.

The vial 94 is a conventional pharmaceutical vial 94 sized to hold thesolid component 96 and a pre-defined volume of the liquid component 100,i.e., the volume of liquid component 100 pre-filled in the syringe 98.The vial 94 includes a septum 134 configured to be pierced andpenetrated by the needles 120 and 126 when the vial 94 is properlypositioned within the first compartment 106.

To aid in positioning and securing of the vial 94 within the compartment106, the applicator 92 includes a selectively removable cap 114, aspreviously noted. The cap 114 mates with the applicator 92, e.g., bysnap-fit engagement with the flanged region 112 on the applicator 92.Desirably (see FIG. 6), the cap 114 extends into the first compartment106 to position and hold the vial 94 in a desired position after theseptum 134 has been pierced by the needles 120 and 126.

In use (see FIGS. 5 and 6), the physician (or assistant) removes the cap114 from the applicator 92. As seen in FIG. 5, with the cap 114 removed,the physician slides the first compartment 106 over the vial 94. Duringthis step, the vial 94 can be placed on a counter, table, or other flatsupport surface. As seen in FIG. 6, the cap 114 is then placed beneaththe vial 94 (e.g., on the counter or table), and the physician continuesto slide the first compartment 106 over the vial 94, to finish piercingthe vial septum 134 with the needles 120 and 126 and locating the vial94 fully into the first compartment 106. The cap 114 thereafter holdsthe vial 94 in this position.

As shown in FIG. 7, the cap 119 is then removed from the syringe 98 andresidual air is expressed from the syringe 98, e.g., by holding thesyringe 98 with the dispensing end 116 upright and gently tapping thesyringe 98 until essentially all of the residual air rises to thedispensing end 116 and then advancing the plunger 102 until the air isexpelled (not shown).

As FIG. 7 shows, the syringe 98 is then placed within the secondcompartment 108 and rotated (represented by an arrow) to couple thesyringe 98 to the first needle 120 through luer fittings 118 and 122.With the syringe 98 and vial 94 in place within the applicator 92 andthe formative assembly 40 ready for use, as seen in FIG. 8, the assembly40 can then be coupled to the mixing assembly 38 (shown in phantomlines) by coupling (represented by arrows) luer fittings 42 and 132.

As will be apparent, alternatively, the syringe 98 can be coupled to thefirst needle 120 prior to the vial 94 being placed in the firstcompartment 106.

With reference now to FIG. 9, the formative component assembly 40 isthen placed in an upright position (i.e., vial septum 134 pointingupward and dispensing end 116 of the syringe 98 pointing downward). Theplunger 102 is then advanced (represented by an arrow) to transfer thecontents of the syringe 98 through the first needle 120 into the vial94. If desired, the assembly 18 can be stood on a counter, table, orother flat surface as the plunger 102 is advanced. Alternatively, theplunger 102 can be advanced in conventional fashion by the thumb of thephysician while the syringe 98, with attached applicator 92, are heldbetween the forefinger and middle finger, as FIG. 9 shows.

The propulsion of the liquid component 100 into the vial 94reconstitutes the solid component 96, mixes the components 96 and 100(represented by arrows in FIG. 9), and begins the reaction process.

Fluid pressure created by operation of the syringe 98 urges the mixtureinto and through the second needle 126, into the mixing 38, as indicatedby arrows in FIG. 10. The mixing assembly 38 further mixes the mixtureand rids the fluid path of residual air, as previously described. Themixture flows through the mixing assembly 38 and through the knot pusherpassage 20. The mixture exits the knot pusher 12 through the distal end16, as FIG. 22 shows.

With reference now to FIG. 11, the plunger 102 is advanced untilessentially all of the liquid component 100 is transferred from thesyringe 98 to the vial 94. Generally concurrently, the mixture istransferred from the vial 94 into the mixing assembly 38, with onlyminimal residual mixture remaining in the vial 94. As will apparent toone skilled in the art, the volume of components 96 and 100 arecalculated to account for this residual volume.

Further details of the component introducer/mixer assembly 30 justdescribed are disclosed in copending U.S. patent application Ser. No.10/141,510, filed May 8, 2002 and entitled “Systems, Methods, andCompositions for Achieving Closure of Vascular Puncture Sites,” which isincorporated herein by reference.

Alternatively (see FIG. 12 to 15), the formative component assembly 40can comprise individual syringes 54 and 56 in which the components areseparately contained. The syringes 54 and 56 are, in use, coupled to aholder 58. In use, the holder 58 is coupled via a luer fitting 59 to themixer element 38, as FIG. 15 shows. Further details of this arrangementare disclosed in copending U.S. patent application Ser. No. 09/187,384,filed Nov. 6, 1998 and entitled “Systems and Methods for ApplyingCross-Linked Mechanical Barriers,” which is incorporated herein byreference.

3. The Material Composition

The components 96 and 100 of the material composition can vary. In apreferred embodiment, the solid component 96 comprises an electrophilic(electrode withdrawing) material having a functionality of at leastthree. The liquid component 100 comprises a solution containing anucleophilic (electron donator) material and a buffer. When mixed underproper reaction conditions, the electrophilic material and bufferednucleophilic material react, by cross-linking with each other. Thecross-linking of the components form the composition. The compositionphysically forms a mechanical barrier (see FIG. 24), which can also becharacterized as a hydrogel.

The type and concentration of a buffer material controls the pH of theliquid and solid components 100 and 96, when brought into contact formixing. The buffer material desirably establishes an initial pH innumeric terms, as well regulates change of the pH over time.

The Electrophilic Component

In its most preferred form, the electrophilic (electrode withdrawing)material 96 comprises a hydrophilic, biocompatible polymer that iselectrophilically derivatized with a functionality of at least three.Examples include poly(ethylene glycol), poly(ethylene oxide), poly(vinylalcohol), poly(vinylpyrrolidinone), poly(ethyloxazoline), andpoly(ethylene glycol)-co-poly(propylene glycol) block copolymers.

As used herein, a polymer meeting the above criteria is one that beginswith a multiple arm core (e.g., pentaerythritol) and not a bifunctionalstarting material, and which is synthesized to a desired molecularweight (by derivatizing the end groups), such that polymers withfunctional groups greater than or equal to three constitute (accordingto gel permeation chromatography—GPC) at least 50% or more of thepolymer blend.

The material 96 is not restricted to synthetic polymers, aspolysaccharides, carbohydrates, and proteins could be electrophilicallyderivatized with a functionality of at least three. In addition, hybridproteins with one or more substitutions, deletions, or additions in theprimary structure may be used as the material 96. In this arrangement,the protein's primary structure is not restricted to those found innature, as an amino acid sequence can be synthetically designed toachieve a particular structure and/or function and then incorporatedinto the material. The protein of the polymer material 96 can berecombinantly produced or collected from naturally occurring sources.

Preferably, the polymer material 96 is comprised of poly(ethyleneglycol) (PEG) with a molecular weight preferably between 9,000 and12,000, and most preferably 10,500±1500. PEG has been demonstrated to bebiocompatible and non-toxic in a variety of physiological applications.The preferred concentrations of the polymer are 5% to 35% w/w, morepreferably 5% to 20% w/w. The polymer can be dissolved in a variety ofsolutions, but sterile water is preferred.

The most preferred polymer material 96 can be generally expressed ascompounds of the formula:

PEG-(DCR-CG)_(n)

-   -   Where:    -   DCR is a degradation control region.    -   CG is a cross-linking group.    -   n≧3

The electrophilic CG is responsible for the cross-linking of thepreferred nucleophilic material 96, as well as binding the composition136 to the like material in the surrounding tissue, as will be describedlater. The CG can be selected to selectively react with thiols,selectively react with amines, or react with thiols and amines. CG'sthat are selective to thiols include vinyl sulfone, N-ethyl maleimide,iodoacetamide, and orthopyridyl disulfide. CG's that are selective toamines include aldehydes. Non-selective electrophilic groups includeactive esters, epoxides, oxycarbonylimidazole, nitrophenyl carbonates,tresylate, mesylate, tosylate, and isocyanate. The preferred CG's areactive esters, more preferred, an ester of N-hydroxysuccinimide. Theactive esters are preferred since they react rapidly with nucleophilicgroups and have a non-toxic leaving group, e.g., hydroxysuccinimide.

The concentration of the CG in the polymer material 96 can be used tocontrol the rate of gelation. However, changes in this concentrationtypically also result in changes in the desired mechanical properties ofthe hydrogel.

The rate of degradation is controlled by the degradation control region(DCR), the concentration of the CG's in the polymer solution, and theconcentration of the nucleophilic groups in the protein solution.Changes in these concentrations also typically result in changes in themechanical properties of the hydrogel, as well as the rate ofdegradation.

The rate of degradation (which desirably occurs in about 30 days) isbest controlled by the selection of the chemical moiety in thedegradation control region, DCR. If degradation is not desired, a DCRcan be selected to prevent biodegradation or the material can be createdwithout a DCR. However, if degradation is desired, a hydrolytically orenzymatically degradable DCR can be selected. Examples of hydrolyticallydegradable moieties include saturated di-acids, unsaturated di-acids,poly(glycolic acid), poly(DL-lactic acid), poly(L-lactic acid),poly(ξ-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone),poly(amino acids), poly(anhydrides), poly(orthoesters),poly(orthocarbonates), and poly(phosphoesters), and derivatives thereof.A preferred hydrolytically degradable DCR is gluturate. Examples ofenzymatically degradable DCR's include Leu-Gly-Pro-Ala (collagenasesensitive linkage) and Gly-Pro-Lys (plasmin sensitive linkage). Itshould also be appreciated that the DCR could contain combinations ofdegradable groups, e.g. poly(glycolic acid) and di-acid.

While the preferred polymer is a multi-armed structure, a linear polymerwith a functionality, or reactive groups per molecule, of at least threecan also be used. The utility of a given PEG polymer significantlyincreases when the functionality is increased to be greater than orequal to three. The observed incremental increase in functionalityoccurs when the functionality is increased from two to three, and againwhen the functionality is increased from three to four. Furtherincremental increases are minimal when the functionality exceeds aboutfour.

A preferred polymer may be purchased from SunBio Company ((PEG-SG)₄,having a molecular weight of 10,500±1500) (which will sometimes becalled the “SunBio PEG”).

The Nucleophilic Component

In a most preferred embodiment, the nucleophilic material 100 includesnon-immunogenic, hydrophilic proteins. Examples include serum, serumfractions, and solutions of albumin, gelatin, antibodies, fibrinogen,and serum proteins. In addition, water soluble derivatives ofhydrophobic proteins can be used. Examples include solutions ofcollagen, elastin, chitosan, and hyaluronic acid. In addition, hybridproteins with one or more substitutions, deletions, or additions in theprimary structure may be used.

Furthermore, the primary protein structure need not be restricted tothose found in nature. An amino acid sequence can be syntheticallydesigned to achieve a particular structure and/or function and thenincorporated into the nucleophilic material 100. The protein can berecombinantly produced or collected from naturally occurring sources.

The preferred protein solution is 25% human serum albumin, USP. Humanserum albumin is preferred due to its biocompatibility and its readyavailability.

The uses of PEG polymers with functionality of greater than threeprovides a surprising advantage when albumin is used as the nucleophilicmaterial 100. When cross-linked with higher functionality PEG polymers,the concentration of albumin can be reduced to 25% and below. Past usesof difunctional PEG polymers require concentrations of albumin wellabove 25%, e.g. 35% to 45%. Use of lower concentrations of albuminresult in superior tissue sealing properties with increased elasticity,a further desired result. Additionally, 25% human serum albumin, USP iscommercially available from several sources, however higherconcentrations of human serum albumin, USP are not commerciallyavailable. By using commercially available materials, the dialysis andultrafiltration of the albumin solution, as disclosed in the prior art,is eliminated, significantly reducing the cost and complexity of thepreparation of the albumin solution.

To minimize the liberation of heat during the cross-linking reaction,the concentration of the cross-linking groups of the fundamental polymercomponent is preferably kept less than 5% of the total mass of thereactive solution, and more preferably about 1% or less. The lowconcentration of the cross-linking group is also beneficial so that theamount of the leaving group is also minimized. In a typical clinicalapplication, about 50 mg of a non-toxic leaving group is produced duringthe cross-linking reaction, a further desired result. In a preferredembodiment, the CG comprising an N-hydroxysuccinimide ester hasdemonstrated ability to participate in the cross-linking reaction withalbumin without eliciting adverse immune responses in humans.

The Buffer Component

In the most preferred embodiment, a PEG reactive ester reacts with theamino groups of the albumin and other tissue proteins, with the releaseof N-hydroxysuccinimide and the formation of a link between the PEG andthe protein. When there are multiple reactive ester groups per PEGmolecule, and each protein has many reactive groups, a network of linksform, binding all the albumin molecules to each other and to adjacenttissue proteins.

This reaction with protein amino groups is not the only reaction thatthe PEG reactive ester can undergo. It can also react with water (i.e.,hydrolyze), thereby losing its ability to react with protein. For thisreason, the PEG reactive ester must be stored dry before use anddissolved under conditions where it does not hydrolyze rapidly. Thestorage container for the PEG material desirably is evacuated by use ofa vacuum, and the PEG material is stored therein under an inert gas,such as Argon or Nitrogen. Another method of packaging the PEG materialis to lyophilize the PEG material and store it under vacuum, or under aninert gas, such as Argon or Nitrogen, as will be described in greaterdetail later. Lyophilization provides the benefits of long term storageand product stability, as well as allows rapid dissolution of the PEGmaterial in water.

The conditions that speed up hydrolysis tend to parallel those thatspeed up the reaction with protein; namely, increased temperature;increased concentration; and increased pH (i.e., increased alkali). Inthe illustrated embodiment, temperature cannot be easily varied, sovarying the concentrations and the pH are the primary methods ofcontrol.

It has been discovered, through bench testing, that when cross-linkingthe SunBio PEG with albumin (Plasbumin), a range of gelation timesbetween an acceptable moderate time (about 30 seconds) to a rapid time(about 2 seconds) can be achieved by establishing a pH range from about8 (the moderate times) to about 10 (the rapid times). Ascertaining thecross-linking pH range aids in the selection of buffer materials fromamong phosphate, tris-hydroxymethylaminomethane (Tris), and carbonate,which are all non-toxic, biocompatible buffers.

Further details of the material composition are found in copending U.S.patent application Ser. No. 09/780,014, filed Feb. 9, 2001, and entitled“Systems, Methods, and Compositions for Achieving Closure of VascularPuncture Sites,” which is incorporated herein by reference.

Representative Embodiment

In a representative embodiment employed with a 7 FR device, the vial 94contains 600 mg±10% of lyophilized SunBio PEG-SG (4-arm polyethyleneglycol tetrasuccinimidyl glutarate—MW 10,500±1500). Details of thelyophilization process are described in U.S. patent application Ser. No.10/141,510, filed May 8, 2002 and entitled “Systems, Methods, andCompositions for Achieving Closure of Vascular Puncture Sites,” which isincorporated herein by reference. The syringe 98 contains 6 ml of waterand 2 ml of buffered 25% w/w human serum albumin, USP. The buffered 25%albumin is made by adding 0.217 g. of Tris-hydroxymethlaminomethane(C₄H₁₁NO₃) (FW 121.1) (TRIS Buffer) to 20 cc of Bayer Plasbumin®-25 toobtain a pH between 8.0 and 8.7, most preferably between 8.3 and 8.5.

II. Representative Use of the System

Use of the knot pusher 12 in conventional fashion will form the sutureclosure 28, as FIGS. 16 to 21 show. As FIG. 22 shows, once coupled tothe knot pusher 12, operation of the formative component assembly 40, aspreviously described, expresses the components 96 and 100, while inliquid form, through the mixer element 38 and through the knot pusher12. The gelating components 50 flow out the distal end 16 and slot 22 ofthe knot pusher and into the subcutaneous tissue surrounding the sutureclosure 28.

The knot pusher 12 is desirably sized to seal the tissue track 34, toblock substantial flow in a path up the tissue track 34. Thus, thegelating components 50 are first delivered in a liquid state adjacent tothe suture closure 28. The incoming flow, directed in this manner,creates a tissue space about the suture closure 28. The gelatingcomponents 50 fill this space. Desirably (see FIG. 23), after firstintroducing the gelating components 50 at the site of the suture closure28, the physician slowly withdraws the knot pusher 12 up the tissuetract 34 while still delivering the components 50, to substantially fillthe entire tissue tract 34 with the gelating components 50.

In the gelation process, the electrophilic component and thenucleophilic component cross-link, and the developing composition 50gains cohesive strength to close the suture closure 28 and the tissuetract 34. The electrophilic component also begins to cross-link withnucleophilic groups on the surrounding tissue mass. Adhesive strengthforms, which begins to adhere the developing composition to thesurrounding tissue mass.

During the introduction stage, before internal cohesive and tissueadhesive strengths fully develop, a portion of the gelating components50 can seep through the suture closure 28 and enter the blood vessel.Upon entering the blood stream, the gelating components 50 willimmediately experience physical dilution. The dilution expands thedistance between the electrophilic component and the nucleophiliccomponent, making cross-linking difficult. In addition, the dilutedcomponents now experience an environment having a pH (7.3 to 7.4) lowerthan the an effective reactive pH for cross-linking (which is above 8)(as an example, a typical gelation time at pH 8.3 is about 15 to 20seconds, whereas a typical gelation time at pH 7.4 is over 10 minutes).As a result, incidence of cross-linking within the blood vessel, to formthe hydrogel composition, is only a fraction of what it is outside thevessel, where gelation continues.

Furthermore, the diluted electrophilic component will absorbnucleophilic proteins present in the blood. This reaction furtherreduces the reactivity of the electrophilic component. In blood, thediluted electrophilic component is transformed into a biocompatible,non-reactive entity, which can be readily cleared by the kidneys andexcreted. The diluted nucleophilic component 100 is a naturallyoccurring protein that is handled in normal ways by the body.

This stage preferably last about 5 to 30 seconds from the time thephysician begins to mix the components 96 and 100.

A second stage begins after the physician has delivered the entireprescribed volume of components 96 and 100 to the tissue mass of thesuture closure 28 and tissue tract 34. At this point, the cross-linkingof the components 96 and 100 has progressed to the point where asemi-solid gel occupies the formed tissue space. The physician can nowapplies localized and temporary compression to the exterior skin surfacesurrounding the tissue track 34.

The application of localized pressure serves two purposes. It is not toprevent blood flow through the tissue track 34, as cross-linking of thecomponents 96 and 100 has already proceeded to create a semi-solid gelhaving sufficient cohesive and adhesive strength to impede blood flowfrom the puncture site. Rather, the localized pressure serves tocompress the tissue mass about the semi-solid gel mass. This compressionbrings the semi-solid gel mass into intimate contact with surroundingtissue mass, while the final stages of cross-linking and gelation takeplace.

Under localized compression pressure, any remnant track of the knotpusher 12 existing through the gel mass will also be closed.

Under localized compression pressure, surface contact between theadhesive gel mass and tissue is also increased, to promote thecross-linking reaction with nucleophilic groups in the surroundingtissue mass. Adhesive strength between the gel mass and tissue isthereby allowed to fully develop, to firmly adhere the gel mass to thesurrounding tissue as the solid composition 50 forms in situ.

During this stage, blood will also contact the vessel-side, exposedportion of the gel mass, which now covers the tissue puncture site. Theelectrophilic component will absorb nucleophilic proteins present in theblood, forming a biocompatible surface on the inside of the vessel.

The second stage preferably last about 3 to 10 minutes from the time thephysician withdraws the knot pusher 12. At the end of the second stage,the solid composition 50 has formed (as FIG. 24 shows). Hemostasis hasbeen achieved. The suture ends S1 and S2 can be trimmed at the skinsurface, and the individual is free to ambulate and quickly return tonormal day-to-day functions.

The mechanical properties of the solid composition 50 are such to form amechanical barrier. The composition 50 is well tolerated by the body,without invoking a severe foreign body response. Over a controlledperiod, the material composition 50 is degraded by physiologicalmechanisms. As the material is degraded, the tissue returns to aquiescent state. The molecules of the degraded genus hydrogelcomposition are cleared from the bloodstream by the kidneys andeliminated from the body in the urine. In a preferred embodiment of theinvention, the material loses its physical strength during the firstfifteen days, and totally resorbs in about four to eight weeks,depending upon the person's body mass.

III. Alternative Embodiment

FIG. 25 shows an alternative embodiment of a knot pusher 60 for theclosure of incisions and wounds using a suture knot in combination witha biocompatible material composition. Like the knot pusher 12, the knotpusher 60 is well suited for use, for example, at a vascular puncturesite following a vascular access procedure. In use (see FIGS. 29 and30), like the knot pusher 12, the knot pusher 60 accommodates couplingto a component introducer/mixer assembly 30 of the type shown in eitherFIG. 1 or FIG. 15, to introduce a biocompatible material composition tothe site of a suture closure 28 through a transcutaneous tissue tract34. In FIGS. 29 and 30, an assembly 30 of the type shown in FIG. 15 isshown for purposes of illustration.

In the embodiment shown in FIG. 25, the knot pusher 60 comprises acoaxial assembly of an outer sheath 62 and an inner knot pushing element64. A lumen 66 in the outer sheath 62 accommodates passage of the knotpushing element 64, as FIG. 26 shows. The lumen 66 includes an opendistal end 76 and a port 78 at the proximal end, to which the assembly30 is coupled during use (as shown in FIG. 29). In this arrangement (seeFIG. 31), a passage 68 is formed between the exterior of the knotpushing element 64 and the interior wall of the lumen 66. The port 78and open distal end 76 communicate with the passage 68. As will bedescribed later, it is through this passage 68 that the materialcomposition 50 is introduced.

Like the knot pusher 12, the knot pusher 60 comprises an elongated bodyor shaft 70 having a distal end 72. The shaft 14 is sized and configuredfor passage through the lumen 66 of the outer sheath. It is also sizedand configured, when passed through the lumen 66, to have its distal end72 extend beyond the open distal end 76 of the outer sheath 62, as FIG.26 shows.

Unlike the knot pusher 12, the knot pusher 60 does not include athrough-passage to conduct the biocompatible material composition 50.Instead, in use, the biocompatible material composition is conductedthrough the passage 68 that is formed between the knot pushing element64 and the interior wall of the lumen 66.

The knot pusher 60 includes a suture threading fixture 24 of the typepreviously described in association with the knot pusher 12. The fixture24 can be releasably carried by the distal end 72 of the shaft 70 inalignment with a slotted passage 74 in the distal end 72 of the shaft70.

The fixture 24 likewise includes a threader 26 of a type previouslydescribed. As before described, the threader 26 desirably comprises aloop of thin, flexible wire that is initially positioned so as to passthrough the slotted passage 74 and out the distal end 72 of the shaft70.

In use, with the fixture 24 unattached, the knot pushing element 64 ispassed through the lumen 66 of outer sheath 62. The threader 26 can thenbe passed through the slotted passage 74, which is exposed beyond thedistal end 76 of the outer sheath 62. If desired, the fixture 24 canalso be releasably secured to the distal end 72 of the knot pushingelement 64 (as FIG. 26 shows).

After the slidable knot 18 is formed (as previously described), theattending physician captures a free end S1 of the suture within the loopof the threader 26 (as FIG. 27 shows) . Freeing the fixture 24 from thedistal end 72, the physician pulls the fixture 24 distally to draw thethreader 26 and, with it, the free end S1 of the suture through theslotted passage 74. Upon releasing the free end S1 of the suture fromthe threader 26, and discarding the fixture 24, the physician can thenurge the knot pushing element 64 and the outer sheath 62 as an assembledunit through the tissue tract 34 (as FIG. 28 shows). Holding the freesuture end S1, the physician advances the assembled knot pusher 60 totighten the slidable knot 18 within the tissue tract 34, as FIG. 28shows. The knot pusher 60 engages and advances the slidable knot 18 overthe free end Si of the suture, to close the suture loop 20 and bring theedges of the puncture site 36 into apposition. The slidable knot 18 canthen be tightened by pulling on the other free end S2 of the suture,forming a suture closure 28 (shown in FIG. 28). In this arrangement, thesuture end S1 serves as a guide wire, to locate and guide the assembledknot pusher 60 generally over the center of the suture closure 28.

Upon forming the suture closure 28 using the knot pusher 60 in themanner just described, the component introducer/mixer assembly 30 can beassembled and coupled to the port 78 of the outer sheath 62(see FIG.29). The assembly 30 is manipulated in the manner previously describedto introduce a biocompatible material composition 50 through the passage68 and out the open distal end 76 of the outer sheath 62. Thecomposition 50 is placed about the suture closure 28 outside the bloodvessel. Desirably (see FIG. 30), by simultaneously withdrawing the knotpusher 60 up the tissue tract 34 as the composition 50 is conducted outthe open distal end 76, the composition 50 can also be placed in atleast portion of the tissue tract 34. Most desirably (as FIG. 30 shows),at the end of the procedure, the composition 50 fills the tissue tract34.

As already described, the biocompatible material composition 50desirably produces a solid, three dimensional matrix that preventsseepage of blood and fluids through the suture closure 28 and up thetissue tract 34. The knot pusher 60 thereby creates a dry closure, whichis substantially free of blood or fluid leakage about the suture closure28 and in the tissue tract 34.

The foregoing is considered as illustrative only of the principles ofthe invention. Furthermore, since numerous modifications and changeswill readily occur to those skilled in the art, it is not desired tolimit the invention to the exact construction and operation shown anddescribed. While the preferred embodiment has been described, thedetails may be changed without departing from the invention, which isdefined by the claims.

1. Apparatus comprising a first component sized and configured to place a suture loop through tissue to join tissue and to tie the suture loop to form a suture knot, and a second component sized and configured to discharge a liquid closure material comprising an electrophilic component comprising a hydrophilic, biocompatible polymer that is electrophilically derivatized with a functionality of at least three and a solution containing a nucleophilic component comprising recombinant or natural serum albumin in a concentration of 25% or less and a buffer component adjacent the suture knot, the liquid closure material cross-linking after discharge to form a solid closure adjacent the suture knot having cohesive and tissue adhesive strength to impede blood flow without clot formation.
 2. Apparatus according to claim 1 wherein the first component comprises a knot pusher.
 3. Apparatus according to claim 2 wherein the second component is carried by the knot pusher.
 4. Apparatus according to claim 1 wherein the polymer comprises poly(ethylene glycol) (PEG).
 5. Apparatus according to claim 1 wherein the recombinant or natural serum albumin comprises human serum albumin. 